Lincoln Scofield is on death row for the murder of the vice president's brother. He insists he's innocent, but only his brother Michael believes him. An engineer who helped design the prison where Lincoln is being held, Michael takes drastic measures to help his brother. He gets himself arrested and sent to the same prison, so that with his knowledge of the building the two of them can escape together. However, while inside Michael discovers a massive conspiracy that is determined to see Lincoln's sentence carried out. Breaking out will be more difficult than he thought, but he's still going to try.

Overcoming many setbacks, Michael, Lincoln and six other inmates, ultimately escaped from Fox River. The prison break had its consequences, however. Outside the prison walls, the escape truly begins as the convicts race for their lives – and $5 million in hidden cash – while trying to avoid capture by the authorities. The pursuers are led by FBI agent Alex Mahone, who is haunted by his own demons; vengeful prison guard Captain Bellick, who, driven by his own personal vendetta, will also stop at nothing until the escapees are captured or killed; and Secret Service Agent Paul Kellerman, who, under President Reynolds' orders, will do anything to keep the truth about the conspiracy very much a secret.

After a former Company employee exonerates Lincoln, Michael, T-Bag and Mahone are arrested by the Panamanian authorities and are imprisoned at the Penitenciaría Federal de Sona where they find Bellick. Burrows is contacted by The Company who have kidnapped his son LJ and Sara Tancredi and is told that they want Scofield to break James Whistler out of Sona. After failing to comply, Sara is seemingly killed. Most manage to escape and Michael sets out to bring about the fall of the Company.

Donald Self, a Department of Homeland Security agent, recruits Michael and Lincoln as well as Sucre, Bellick and Mahone for their help to bring down the Company in exchange for their freedom. Sara remains alive and reunites with Michael. Together, this team devises a plan to retrieve data from the Company that will help to destroy the Company. As an operative hunts them down, T-Bag takes another man's identity and seeks revenge on Michael.